Hepatitis C virus induced endothelial inflammatory response depends on the functional expression of TNFα receptor subtype 2

• Published in: PloS one Vol. 9; no. 11; p. e113351
• Main Authors: Pircher, Joachim, Czermak, Thomas, Merkle, Monika, Mannell, Hanna, Krötz, Florian, Ribeiro, Andrea, Vielhauer, Volker, Nadjiri, Jonathan, Gaitzsch, Erik, Niemeyer, Markus, Porubsky, Stefan, Gröne, Hermann-Josef, Wörnle, Markus
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.11.2014; Public Library of Science (PLoS)
• Subjects: Adhesion; Animals; Biology and Life Sciences; Blood; Blotting, Western; Cancer; Cell activation; Cell migration; Cell Proliferation - drug effects; Cells, Cultured; Cytokines; Cytokines - genetics; Cytokines - metabolism; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - virology; Endothelium; Experiments; Extravasation; Gene expression; Gene Expression - drug effects; Heart; Hepacivirus - genetics; Hepacivirus - physiology; Hepatitis; Hepatitis C; Hepatitis C virus; Host-Pathogen Interactions; Humans; Immune system; Infections; Infiltration; Inflammation; Inflammatory response; Innate immunity; Interferon; Interferon-Induced Helicase, IFIH1; Leukocyte rolling; Leukocyte Rolling - drug effects; Leukocytes; Medical research; Medicine; Medicine and Health Sciences; Metastases; Mice, Inbred C57BL; Mice, Knockout; Morbidity; Poly (I:C); Poly I-C - pharmacology; Polyinosinic:polycytidylic acid; Receptors; Receptors, Tumor Necrosis Factor, Type II - genetics; Receptors, Tumor Necrosis Factor, Type II - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA Interference; Rodents; Time Factors; TLR3 protein; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Toll-like receptors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Viral infections; Viruses; White blood cells; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113351

In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I:C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFα). HCV-RNA induces the endothelial expression of TNFα and TNFα receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections.